Famciclovir (Page 5 of 7)

12.4 Microbiology

Mechanism of action: Famciclovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, α-herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown.

Antiviral activity: In cell culture studies, penciclovir has antiviral activity against the following herpes viruses: HSV-1, HSV-2 and VZV. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV and 10 days postinfection for VZV. The median EC50 values of penciclovir against laboratory and clinical isolates of HSV-1, HSV-2 and VZV were 2 μM (range 1.2 to 2.4 μM, n = 7) and 2.6 μM (range 1.6 to 11 μM, n = 6), and 34 μM (range 6.7 to 71 μM, n=6), respectively.

Resistance:

In Cell Culture

Penciclovir-resistant HSV-1 and HSV-2 strains were isolated in cell culture. Penciclovir-resistant mutants of HSV and VZV resulted from mutations in the viral thymidine kinase (TK) and DNA polymerase (POL) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with decreased enzymatic activity and consequent decreased susceptibility to penciclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture, the following resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed: HSV-1 TK G6C, F13L, H142Y, G200D, L205S, S254Stop, V267G, and T287M; HSV-2 TK G39E, F191L, E226K, and T288M. The median EC50 values observed in a plaque reduction assay with penciclovir resistant HSV-1, HSV-2, and VZV were 69 μM (range 14 to 115 μM, n=6), 46 μM (range 4 to > 395 μM, n=9), and 92 μM (range 51 to 148 μM, n=4), respectively.

Resistance and Cross-resistance in Clinical Isolates from HSV-Infected Patients.

Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment with acyclovir for their α-herpesvirus infections were evaluated for genotypic changes in the TK and POL genes. These HSV isolates had frameshift mutations leading to loss of thymidine kinase or had substitutions in the viral thymidine kinase and viral DNA polymerase. Phenotypic analysis of these clinical isolates confirmed resistance to penciclovir and acyclovir. These and other resistance-associated substitutions reported in the literature, or observed in clinical trials, are listed in Table 6. The list is not all inclusive and additional changes will likely be identified in HSV variants isolated from patients who fail penciclovir containing regimens. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.

Table 6: Summary of Known HSV TK and POL Amino Acid Substitutions Conferring Resistance to Acyclovir and Cross-Resistance to Penciclovir

* These substitutions were also observed in penciclovir-treated patients.

HSV-1 TK G6C, R32H, R51W, Y53C/H, H58N, G59W, G61A, S74Stop, E83K, P84L, T103P, Q104Stop, D116N, M121R, I143V, R163H, L170P, Y172C, A174P, R176Q/W, Q185R, A189V, G200D, G206R, L208H, R216C, R220H, R222C/H, FS 224, Y239S, T245M, Q250Stop, S254Stop, R256W, Q261Stop, R281Stop, T287M, L315S, M322K, C336Y
HSV-2 TK G39E, R51W, Y53N, R177W*, R221H, T288M*
HSV-1 POL A657T, D672N, V715G, A719V, S724N, E798K, V813M, N815S, Y818C, G841S, R842S, F891C, V958L
HSV-2 POL

Note: Many additional pathways to penciclovir resistance likely exist.

Cross-resistance has been observed among HSV isolates carrying foscarnet resistance-associated substitutions (Table 7).

Table 7: Summary of Known HSV-1 POL Amino Acid Substitutions Conferring Resistance to Foscarnet and Cross- Resistance to Penciclovir
HSV-1 POL D672N, S724N, E798K, V813M, Y818C, F891C, V958L

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Two-year dietary carcinogenicity studies with famciclovir were conducted in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in animals of this strain) was seen in female rats receiving the high dose of 600 mg/kg/day (1.1 to 4.5x the human systemic exposure at the recommended total daily oral dose ranging between 500 mg and 2000 mg, based on area under the plasma concentration curve comparisons [24 hr AUC] for penciclovir). No increases in tumor incidence were reported in male rats treated at doses up to 240 mg/kg/day (0.7 to 2.7x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.3 to 1.2x the human AUC).

Mutagenesis: Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential in a battery of in vitro and in vivo assays. Famciclovir and penciclovir were negative in in vitro tests for gene mutations in bacteria (S. typhimurium and E. coli) and unscheduled DNA synthesis in mammalian HeLa 83 cells (at doses up to 10,000 and 5,000 mcg/plate, respectively). Famciclovir was also negative in the L5178Y mouse lymphoma assay (5000 mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat dominant lethal study (5000 mg/kg). Famciclovir induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage (1200 mcg/mL). Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation (1000 mcg/mL). In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation (250 mcg/mL). Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow (500 mg/kg), but not when administered orally.

Impairment of fertility: Testicular toxicity was observed in rats, mice, and dogs following repeated administration of famciclovir or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm count, and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity to male reproduction was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of dosing at 500 mg/kg/day (1.4 to 5.7x the human AUC). The no observable effect level for sperm and testicular toxicity in rats following chronic administration (26 weeks) was 50 mg/kg/day (0.15 to 0.6 x the human systemic exposure based on AUC comparisons). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26 weeks) at doses of 600 mg/kg/day (0.3 to 1.2x the human AUC) and 150 mg/kg/day (1.3 to 5.1x the human AUC), respectively.

Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg/day (2.7 to 10.8x the human AUC).

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